Optimal recovery of walking after spinal cord injury (SCI) depends on several factors. Two factors inextricably entwined are the receptivity of the local cellular environment in the spinal cord and the time elapsed since injury. Thus, response to treatment can vary depending on the type of training, when it is initiated and whether a permissive cellular environment exists. This proposal will examine the interaction of these factors to determine the optimal therapeutic window and cellular environment for different forms of task specific training. An innovative aspect of the proposal will be to determine whether eccentric training restores more locomotor recovery than stepping activity alone after moderate/severe SCI (Aim 1). We will use downhill treadmill (TM) training to accentuate eccentric action and uphill TM training to eliminate it and compare outcomes to traditional training on a flat treadmill (TM). Additionally, we will define the optimal therapeutic window for task specific training by comparing training during acute (2-9 days) or late SCI (35-42 days) (Aim 2). The matrix metalloproteinase-9 (MMP-9) has been identified as a key mediator of SCI pathogenesis and an important factor in activity-dependent learning. We will determine whether MMP-9 interacts with task specific training to affect locomotor recovery after SCI (Aim 3). Preliminary evidence suggests that accentuating eccentric activity during training is beneficial but eliminating it via uphill training is quite detrimental. Also, MMP-9 seems to impede task specific training and locomotor recovery early after SCI. Therefore, we hypothesize that eccentric task specific training, delivered either after peak MMP-9 or in conjunction with early pharmacological blockade of MMP-9 will promote optimal locomotor recovery after SCI. PUBLIC HEALTH RELEVANCE: The project will identify the critical determinants of training-induced recovery after experimental spinal cord injury. We will identify which type of task specific training promotes greater recovery, when to begin training and factors in the cellular environment which impede motor relearning and recovery.